Advances in regenerative medicine offer great potential for the treatment of limb amputees. However, despite an increasing understanding of the molecular mechanisms underlying regenerative responses in model systems (e.g., salamander limb regeneration), the application of this knowledge to mammalian systems is lagging. With the ultimate goal of inducing mammalian limb regeneration, we propose here to apply the results gained from recent studies on the wound epidermis formed during salamander limb regeneration to a non-regenerative system, i.e., mouse digit amputation wounds. Specifically, we hypothesize that the murine orthologs of those genes and microRNAs identified in regenerating salamander limbs can initiate mammalian regeneration when ectopically expressed. If successful, the basic knowledge gained from these unprecedented studies will have a significant impact on tissue repair, wound healing and comparative developmental biology. Moreover, this work will provide the foundation for future human limb regeneration clinical applications. PUBLIC HEALTH RELEVANCE: Advances in regenerative medicine offer great potential for the treatment of limb amputees. However, despite an increasing understanding of the molecular mechanisms underlying regenerative responses in model systems (e.g., salamander limb regeneration), the application of this knowledge to mammalian systems is lagging. With the ultimate goal of inducing mammalian limb regeneration, we propose here to apply the results gained from recent studies on the wound epidermis formed during salamander limb regeneration to a non-regenerative system, i.e., mouse digit amputation wounds.